Several lines of evidence suggest that innate immune responses particularly within the gut associated lymphoid tissues (GALT) play a critical role during the acute infection period that delivers an imprint on the level of viremia, setting of the viral load set point and rate of disease progression both in HIV-1 infected humans and the SIV non-human primate model of human AIDS. This concept is supported by the findings from studies that document a) an important role of the cellular lineages that comprise the innate immune system during acute infection, b) the findings from studies of whole genome association that the rate of disease progression is linked with several genes among them is the association with the HLA-C region known to interact with killer cell immunoglobulin inhibitory receptors (KIRs) expressed by NK cells c) Specific KIR alleles influence the effectiveness of NK cell activity in the containment of HIV replication d) our data of a strong association of KIR3DL.11 allele with spontaneous viral load control in SIVmac251 infected Mamu-A01+ rhesus macaques c) our lab derived preliminary data of an association between differences in the kinetics of marked rapid increases during the acute infection period in the frequency and absolute numbers of HLA-E tetramer+ cells that express the gut homing marker alpha4/beta7 in SIV disease-resistant sooty mangabeys. The fact that the kinetics are also faster in SIV-infected long term non-progressor rhesus macaques as compared with MHC haplotype identical SIV-infected regular progressor rhesus macaques underscores the importance of this finding. We submit that a more detailed study of the kinetics of the appearance of sub-lineages of NK cells, the family of KIRs that are expressed and the cytokine/chemokine profile of each of these subsets is warranted. Our ability to functionally deplete this cell lineage in vivo during acute and/or chronic infection using a JAK3 inhibitor combined with our ability to in vitro expand and infuse large number of defined autologous NK cells and track them in vivo provide us with unique and powerful tools to do the subtract/add cell lineage experiments that we submit will provide important clues as to the role this cell lineage plays during the acute and chronic infection period. We submit that the studies outlined will provide important insights on mechanisms by which the innate immune system influences events during the acute infection period and provide avenues that can be exploited for therapeutic benefit of HIV-1 infected humans. PUBLIC HEALTH RELEVANCE: Early events following HIV infection in humans and in the SIV infected monkey model of human AIDS are poorly understood. It is the working hypothesis of this proposal that precise definition of these early events are important since they lay down the ground work with how the level of viremia and rate of disease progression proceeds. Studies are therefore focused on defining these early events in SIV infected monkeys.